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2. An open, prospective trial investigating the pharmacokinetics and safety, and the tolerability of escalating infusion rates of a 10% human normal immunoglobulin for intravenous infusion (IVIg), BT090, in patients with primary immunodeficiency disease

Author

R. Linde, C. Sonnenburg, G. Kriván, Ch. Königs, E. Bernatowska, Abdulgabar Salama, and A. Wartenberg‐Demand

Subjects
Adult, Male, Adolescent, Disease, Drug Administration Schedule, Young Adult, Pharmacokinetics, medicine, Humans, In patient, Prospective Studies, Child, Infusions, Intravenous, Infusion time, business.industry, Immunologic Deficiency Syndromes, Immunoglobulins, Intravenous, Hematology, General Medicine, Middle Aged, medicine.disease, Tolerability, Prospective trial, Immunoglobulin G, Anesthesia, Primary immunodeficiency, Human Normal Immunoglobulin, Female, business, Half-Life
Abstract

Background and Objectives Pharmacokinetics, safety and tolerability of escalating infusion rates of BT090, a 10% intravenous immunoglobulin (IVIg), were studied in patients with primary immunodeficiency disease. Materials and Methods In Part A, patients (n = 30) received 3 infusions of BT090 at their pretrial dose and dosing interval; the infusion rate of BT090 was increased from 0·3 to 1·4 to 2·0 ml/kg/h for each infusion in each patient initially at 30-min intervals. Pharmacokinetics was evaluated at the 3rd infusion (n = 24). At the 4th infusion, infusion rates were to be gradually escalated from 0·3 to 1·4 to 4·0 to a maximum of 8·0 ml/kg/h initially at 30-min intervals to establish the maximum tolerated infusion rate per patient. Results The pharmacokinetic characteristics and safety profile of BT090 were comparable with those of other IVIgs, including Intratect®. Escalation of infusion rates was well tolerated, allowing identification of individual patient's maximum tolerated infusion rate. At subsequent infusions, all patients tolerated their individually defined maximum infusion rate: 17 patients (68·0%) tolerated infusion rates of 6·0 or 8·0 ml/kg/h and four patients (16%) had maximum tolerated infusion rates of

Published
2015

3. Efficacy and safety of home-based subcutaneous immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies

Author

M, Borte, E, Bernatowska, H D, Ochs, C M, Roifman, and S Bobo, Tanner

Subjects
Male, Translational Studies, Injections, Subcutaneous, medicine.medical_treatment, Immunology, Immunoglobulins, Infections, Disease-Free Survival, Immunoglobulin G, Pharmacokinetics, Immunopathology, Humans, Immunology and Allergy, Medicine, Child, Adverse effect, Home Infusion Therapy, biology, business.industry, Immunologic Deficiency Syndromes, medicine.disease, Europe, El Niño, Intravenous therapy, Child, Preschool, North America, biology.protein, Primary immunodeficiency, Female, Antibody, business, Brazil, Follow-Up Studies
Abstract

Summary Subcutaneous immunoglobulin infusions are effective, safe and well tolerated in the treatment of primary immunodeficiencies, but only limited data on the treatment of children are available. We investigated the efficacy, safety and pharmacokinetics of home therapy with a 16% liquid human immunoglobulin G preparation (Vivaglobin®) when administered subcutaneously in children with primary immunodeficiencies. Data were analysed from 22 children (2–

Published
2011

4. Nijmegen breakage syndrome

Author

E. Bernatowska, K.H. Chrzanowska, C.M.R. Weemaes, Dominique Smeets, F.J.M. Gabreëls, J.A.P. Hiel, L.P.W.J. van den Heuvel, B.G.M. van Engelen, and C.J.A.M. van der Burgt

Subjects
Adult, medicine.medical_specialty, Genotype, Radiation Tolerance, Congenital Abnormalities, Consanguinity, Neoplasms, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Registries, business.industry, Facies, Chromosome Breakage, Syndrome, medicine.disease, Nibrin, Common Variable Immunodeficiency, Phenotype, Mutation, Pediatrics, Perinatology and Child Health, General and Specialist Paediatrics, Microcephaly, business, Nijmegen breakage syndrome, Chromosomes, Human, Pair 8
Abstract

BACKGROUND—Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder. NBS-1, the gene defective in NBS, is located on chromosome 8q21 and has recently been cloned. The gene product, nibrin, is a novel protein, which is member of the hMre11/hRad50 protein complex, suggesting that the gene is involved in DNA double strand break repair. AIMS—To study the clinical and laboratory features of NBS as well as the genotype-phenotype relation. METHODS—Fifty five patients with NBS, included in the NBS registry in Nijmegen were evaluated. The majority of the patients were of eastern European ancestry. Most of them had shown a truncating 5 bp deletion 657-661 delACAAA. Four further truncating mutations have been identified in patients with other distinct haplotypes. RESULTS AND CONCLUSIONS—Essential features found in NBS were microcephaly, usually without severe retardation, typical facial appearance, immunodeficiency, chromosomal instability, x ray hypersensitivity, and predisposition to malignancy. In 40% of the patients cancer was noted before the age of 21 years. Important additional features were skin abnormalities, particularly café au lait spots and vitiligo, and congenital malformations, particularly clinodactyly and syndactyly. Congenital malformations, immunodeficiency, radiation hypersensitivity, and cancer predispostion were comprehensible in case of dysfunctioning of DNA repair mechanisms. No specific genotype-phenotype relation could be found. Patients with the same genotype may show different phenotypes and patients with different genotypes may express the same phenotype. Specific mutations did not lead to specific clinical features.

Published
2000

5. Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease

Author

Ron S. Weening, Anders Åhlin, Anthony W. Segal, M de Boer, E Bernatowska-Matuszkiewicz, Futoshi Kuribayashi, JP Hossle, H Middleton-Price, K Nemet, Dirk Roos, and Christof Meischl

Subjects
Genetics, Mutation, Genetic heterogeneity, Genetic enhancement, Immunology, Cell Biology, Hematology, Biology, Compound heterozygosity, medicine.disease, medicine.disease_cause, Biochemistry, Pathogenesis, Chronic granulomatous disease, medicine, CYBB, X chromosome
Published
1996

6. Liver transplantation for severe hepatic graft-versus-host disease in two children after hematopoietic stem cell transplantation

Author

B. Wolska-Kusnierz, Mikołaj Teisseyre, Hor Ismail, E. Bernatowska, Joanna Teisseyre, Joanna Pawłowska, Irena Jankowska, Przemysław Kluge, Małgorzata Markiewicz-Kijewska, Anna Ostoja-Chyzynska, Marek Szymczak, and Piotr Kaliciński

Subjects
Male, Pathology, medicine.medical_specialty, medicine.medical_treatment, Intrahepatic bile ducts, Graft vs Host Disease, chemical and pharmacologic phenomena, Hematopoietic stem cell transplantation, Liver transplantation, Liver disease, immune system diseases, Coagulopathy, Medicine, Humans, Child, Transplantation, business.industry, Vanishing bile duct syndrome, Hematopoietic Stem Cell Transplantation, medicine.disease, Liver Transplantation, surgical procedures, operative, Graft-versus-host disease, Surgery, business, Complication, Immunosuppressive Agents
Abstract

Chronic graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT). After the skin, the liver is the second, most frequent target of GVHD, which presenting with hyperbilirubinemia, elevated liver enzymes, and coagulopathy. Progressive destruction of small intrahepatic bile ducts causes vanishing bile duct syndrome and leads to end-stage liver disease. We report 2 successful cases of orthotopic liver transplantation performed in children with severe GVHD after hematopoietic stem cell transplantation from a matched unrelated donor (HSCT-MUD).

Published
2010

7. Clinical efficacy of intravenous immunoglobulin in patients with severe inflammatory chest disease and IgG3 subclass deficiency

Author

Martina Pum, M. M. Eibl, M. Pac, E. Bernatowska-Matuszkiewicz, and H. Skopcynska

Subjects
Lung Diseases, Male, medicine.drug_class, Immunology, Antibiotics, Immunoglobulin E, Immunopathology, Humans, Immunology and Allergy, Medicine, Prospective Studies, IgG Deficiency, Child, Immunodeficiency, Inflammation, biology, business.industry, Respiratory disease, Immunization, Passive, medicine.disease, Clinical trial, Immunoglobulin M, El Niño, Child, Preschool, Immunoglobulin G, Injections, Intravenous, biology.protein, Female, Dysgammaglobulinemia, Antibody, business, Research Article
Abstract

SUMMARY To investigate the efficacy of i.v. IgG treatment in pediatric patients with inflammatory lung disease, a prospective, controlled clinical trial was carried out over a 2-year study period. Patients were enrolled on the basis of severe clinical symptomatology. After 1 year of conventional treatment, the patients received 400 mg/kg per month of an i.v. IgG product containing only trace amounts of IgG3 in addition to their regular treatment throughout the second year. Significant clinical improvement, as documented by duration of hospital stay (first year 27.8 days, second year 4.9 days), use of antibiotics (132.8 versus 30.9 days) and use of steroids (21.4 versus 0.7 days) could be observed. Data obtained on a subgroup of patients with lgG3 deficiency were analysed separately. These results indicate that patients with severe chest disease who have lgG3 deficiency will also benefit from i.v. IgG treatment. The mode of action cannot be attributed to replacement of the respective isotypes, but is probably due to the effect of i.v. IgG in preventing repeated viral infections.

Published
1991

8. ATM gene founder haplotypes and associated mutations in Polish families with ataxia-telangiectasia

Author

Patrick Concannon, Shareef A. Nahas, Janina Piotrowska-Jastrzębska, G. Sholty, Laura Eng, E. Bernatowska, Sharon N. Teraoka, Midori Mitui, B. Pietrucha, A. Purayidom, and Richard A. Gatti

Subjects
Male, Adolescent, Nonsense mutation, Single-nucleotide polymorphism, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Biology, Protein Serine-Threonine Kinases, medicine.disease_cause, Denaturing high performance liquid chromatography, Ataxia Telangiectasia, Genotype, Genetics, medicine, Missense mutation, Humans, Family, Child, Genetics (clinical), Chromatography, High Pressure Liquid, Polymorphism, Single-Stranded Conformational, Mutation, Tumor Suppressor Proteins, Haplotype, Homozygote, Single-strand conformation polymorphism, Molecular biology, Founder Effect, DNA-Binding Proteins, Haplotypes, Child, Preschool, Female, Poland
Abstract

Summary Ataxia-telangiectasia (A-T) is an early onset autosomal recessive ataxia associated with characteristic chromosomal aberrations, cell cycle checkpoint defects, cancer susceptibility, and sensitivity to ionizing radiation. We utilized the protein truncation test (PTT), and single strand conformation polymorphism (SSCP) on cDNA, as well as denaturing high performance liquid chromatography (dHPLC) on genomic DNA (gDNA) to screen for mutations in 24 Polish A-T families. Twenty-six distinct Short Tandem Repeat (STR) haplotypes were identified. Three founder mutations accounted for 58% of the alleles. Three-quarters of the families had at least one recurring (shared) mutation, which was somewhat surprising given the low frequency of consanguinity in Poland. STR haplotyping greatly improved the efficiency of mutation detection. We identified 44 of the expected 48 mutations (92%): sixty-nine percent were nonsense mutations, 23% caused aberrant splicing, and 5% were missense mutations. Four mutations have not been previously described. Two of the Polish mutations have been observed previously in Amish and Mennonite A-T patients; this is compatible with historical records. Shared mutations shared the same Single Nucleotide Polymorphism (SNP) and STR haplotypes, indicating common ancestries. The Mennonite mutation, 5932 G>T, is common in Russian A-T families, and the STR haplovariants are the same in both Poland and Russia. Attempts to correlate phenotypes with genotypes were inconclusive due to the limited numbers of patients with identical mutations.

Published
2005

9. [Immunity to infection. Infection in primary immunodeficiency]

Author

E, Bernatowska

Subjects
Immunity, Cellular, Immunocompromised Host, Antibody Formation, Immunologic Deficiency Syndromes, Humans, Bacterial Infections, Child, Infections, Immunity, Mucosal, Immunity, Innate
Abstract

The human body has an elaborate system of local and systemic, immune (cellular, humoral) and nonimmune (skin, mucous membranes) defense mechanisms to protect itself against microbal invaders. Disorders of this intricate system of host defense may generally be classified as primary or secondary. Unusual pathogens infect immunocompromised hosts. Ubiquitous organisms can become opportunistic pathogens. Reactivation of latent organisms is common in this group of patients. Despite their unusual features, infections in the primary immunodeficiency do not occur in a haphazard fashion but rather are predictable depending on the type of immune defects.

Published
2002

10. A European phase II study of recombinant human granulocyte colony-stimulating factor (lenograstim) in the treatment of severe chronic neutropenia in children. Lenograstim Study Group

Author

J, Donadieu, P, Boutard, E, Bernatowska, G, Tchernia, G, Couillaud, N, Philippe, and E, Le Gall

Subjects
Adult, Male, Neutropenia, Adolescent, Dose-Response Relationship, Drug, Neutrophils, Infant, Opportunistic Infections, Drug Administration Schedule, Lenograstim, Recombinant Proteins, Hematopoiesis, Colony-Forming Units Assay, Treatment Outcome, Adjuvants, Immunologic, Child, Preschool, Granulocyte Colony-Stimulating Factor, Quality of Life, Humans, Female, Prospective Studies, Child, Follow-Up Studies
Abstract

We conducted a multicentre, open-label prospective study to evaluate the efficacy and tolerability of lenograstim (human-identical glycosylated rHuG-CSF) in the prevention of infectious episodes of severe chronic neutropenia in 19 patients. The median follow up period was 54.6 months. Lenograstim was administered subcutaneously at a starting dosage of 5 microg/kg per day. Neutrophil recovery was achieved in all patients at induction dosages of 5 (n = 15), 10 (n = 2), 15 (n = 1) or 20 microg/kg per day (n = 1) and occurred at a median 7 days after therapy initiation. Alternate-day administration of double-dose lenograstim was feasible in 7 of 17 patients. Lenograstim treatment significantly (P = 0.012) reduced the incidence of treated infections and hospitalization for infection compared with the pre study period and significantly (P0.001) improved perceived health and disease-related symptoms. One patient discontinued treatment because of adverse events (pustulosis) initially related to lenograstim therapy but not confirmed. One patient withdrew by personal choice and was therefore only treated occasionally. One patient committed suicide after 45 months because of social difficulties. One patient was lost during follow up, and three patients presented with a spontaneous neutrophil recovery after 9, 15 and 27 months, respectively. Moderate and transient side-effects related to lenograstim were observed (thrombocytopenia, n = 2; splenomegaly, n = 2; moderate anaemia (without transfusion requirement), n = 5; bone pain, n = 2; increased of alkaline phosphatase, n = 5).Lenograstim produced a sustained neutrophil recovery in patients with severe chronic neutropenia, reduced the incidence and severity of infection, and improved quality of life.

Published
1997

12. Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease

Author

D, Roos, M, de Boer, F, Kuribayashi, C, Meischl, R S, Weening, A W, Segal, A, Ahlin, K, Nemet, J P, Hossle, E, Bernatowska-Matuszkiewicz, and H, Middleton-Price

Subjects
Male, Models, Molecular, X Chromosome, Protein Conformation, Molecular Sequence Data, Genes, Recessive, Cytoplasmic Granules, Granulomatous Disease, Chronic, Genetic Heterogeneity, Interferon-gamma, Consensus Sequence, Leukocytes, Humans, NADH, NADPH Oxidoreductases, Sequence Deletion, Membrane Glycoproteins, Base Sequence, Cell Membrane, NADPH Dehydrogenase, Membrane Transport Proteins, NADPH Oxidases, Genetic Therapy, Cytochrome b Group, Phosphoproteins, Recombinant Proteins, Chromosomes, Human, Pair 1, Mutation, NADPH Oxidase 2, Female, Chromosomes, Human, Pair 16, Chromosomes, Human, Pair 7
Published
1996

13. [Immunization in preterm and term infants]

Author

E, Bernatowska-Matuszkiewicz, J, Socha, E, Gajewska, K, Ceglecka-Tomaszewska, and I, Szczuka

Subjects
Hospitalization, Primary Prevention, Contraindications, Communicable Disease Control, Infant, Newborn, Humans, Infant, Immunization, Infant, Newborn, Diseases
Published
1995

14. Identification of Btk mutations in 20 unrelated patients with X-linked agammaglobulinaemia (XLA)

Author

M. Bobrow, Igor Vorechovsky, Paschalis Sideras, A. D. B. Webster, E. Bernatowska-Matuszkiewicz, David Vetrie, Mauno Vihinen, C. I. E. Smith, Leif Hammarström, and Hong Jin

Subjects
Male, X Chromosome, Genetic Linkage, Molecular Sequence Data, medicine.disease_cause, Agammaglobulinemia, hemic and lymphatic diseases, Genetics, medicine, Agammaglobulinaemia Tyrosine Kinase, Bruton's tyrosine kinase, Humans, RNA, Messenger, Kinase activity, Amino Acids, Molecular Biology, Gene, Genetics (clinical), X chromosome, DNA Primers, Terminator Regions, Genetic, Mutation, biology, Base Sequence, Point mutation, General Medicine, Protein-Tyrosine Kinases, Protein kinase domain, biology.protein, Tyrosine kinase
Abstract

X-linked agammaglobulinaemia (XLA) is an inherited immunodeficiency resulting from mutations in the gene for a cytoplasmic protein tyrosine kinase (Btk). We have utilised reverse-transcription-based PCR in combination with the chemical cleavage and mismatch technique (CCM) to screen for Btk mutations in 42 unrelated patients having classical XLA or 'leaky' XLA-like phenotypes. A variety of mutations, including point mutations, large deletions and splicing defects were detected using this strategy. In total, 20 mutations were found in these patients. All the mutations were different with the exception of three unrelated patients who all showed the same Arg-->His amino acid substitution (R641H) at a highly-conserved residue in the kinase domain. We have also used structural modelling of the Btk kinase domain to predict how two different amino acid substitution mutations at highly-conserved residues are likely to affect the Btk kinase activity.

Published
1995

15. [Antibody deficiency in obstructive lung diseases]

Author

M M, Eibl, M, Pum, E, Bernatowska, and H, Leibl

Subjects
Adolescent, Agammaglobulinemia, Child, Preschool, Humans, Infant, Lung Diseases, Obstructive, IgG Deficiency, Child, Respiratory Tract Infections
Abstract

Severe chronic chest disease is the most serious complication in patients with antibody deficiency syndromes. IgG-subclass-deficiencies were a frequent finding in patients with obstructive lung disease and in patients with sinopulmonary infections. In the patient population referred to us for immunological investigation recurrent infection of the upper and lower respiratory tract was the most common reason to suspect undue susceptibility to infection. In 1034 pediatric patients analyzed 299 were found to be deficient in one of several IgG subclasses. In a group of 30 children, all of whom had severe lung disease and normal concentrations of serum IgG, IgA and IgM, airway-obstruction has been diagnosed in 19. 20 of the 30 patients had IgG-subclass-deficiency. The large percentage of IgG-subclass-deficiencies in this group of patients indicates that immunological disregulation is likely to contribute to the pathogenesis of chronic lung disease.

Published
1990

18. Secretory component, alpha 1-antitrypsin and lysozyme in IgA deficient children. An immunohistochemical evaluation of intestinal mucosa

Author

E. Bernatowska and W.T. Dura

Subjects
Male, Histology, Secretory component, Biopsy, Biology, Esterase, Pathology and Forensic Medicine, Immunoenzyme Techniques, chemistry.chemical_compound, Intestinal mucosa, Humans, Intestinal Mucosa, Child, Immunoglobulin Fragments, Immunoperoxidase, IgA Deficiency, General Medicine, Molecular biology, Staining, Secretory Component, Microscopy, Electron, chemistry, Child, Preschool, alpha 1-Antitrypsin, Immunology, biology.protein, Immunohistochemistry, Female, Muramidase, Dysgammaglobulinemia, Lysozyme, Antibody
Abstract

Nine children with IgA deficiency were studied in order to evaluate by the immunoperoxidase technique the behaviour of secretory component (SC), alpha 1-antitrypsin (alpha 1-AT), lysozyme and esterase in biopsies of intestinal mucosa. In none of the studied patients was SC found to be lacking, suggesting that the epithelial transport mechanism of IgA across enterocytes was relatively normal. The distribution of SC activity in immunodeficient children differed however from that seen in control intestinal mucosa in its non-uniform distribution on the villus, abnormal retention in the Golgi region of enterocytes or exclusive activity confined to the proliferating compartment of the villus. The staining of alpha 1-AT in enterocytes was clearly obvious in all studied cases with no alteration in zonal distribution when compared with normal human mucosa. The lysozyme staining pattern was seen exclusively in Paneth cells. The non-specific esterase positive enterocytes observed in control mucosa failed to stain in biopsies from IgA deficient children. The results of this study of SC, alpha 1-AT, lysozyme and esterase may indicate that IgA deficiency is not related to a defect in enterocyte transport of immunoglobulins and confirms previously reported findings indicating the lymphoid B-cell compartment to be altered.

Published
1984

23. Interaction of campylobacter species with antibody, complement and phagocytes

Author

M Stephenson, D Webster, E Bernatowska, P Jose, and H Davies

Subjects
biology, Phagocytosis, Campylobacter, Gastroenterology, biology.organism_classification, medicine.disease_cause, Campylobacter jejuni, Microbiology, Antibody opsonization, Classical complement pathway, Campylobacter coli, Immunology, biology.protein, medicine, Campylobacter fetus, Antibody, Research Article
Abstract

The opsonisation of four different campylobacter species for human neutrophils was studied using a chemiluminescence system and electron microscopy. Opsonisation of Campylobacter fetus, Campylobacter coli, and Campylobacter jejuni was mediated by antibody and enhanced by complement. Antibody was not, however, required for the phagocytosis of Campylobacter pylori because it activates the classical pathway of complement directly. This unusual property may be important in the pathogenesis of C pylori associated gastritis and duodenal ulcer.

Published
1989

27. Effectiveness of treatment of children with hypogammaglobulinemia: comparison of fresh plasma and intravenous immunoglobulin preparation

Author

E, Bernatowska, R, Weremowicz, W, Janowicz, and K, Madaliński

Subjects
Male, Infection Control, Plasma, Adolescent, Agammaglobulinemia, Child, Preschool, Immunoglobulin G, Injections, Intravenous, Humans, Blood Transfusion, Female, Child
Abstract

Eight children aged 2 to 16 years who were diagnosed as having primary humoral immunodeficiency were treated with fresh plasma substitution, during the first 2 years. Subsequently these children and 5 other children with primary humoral immunodeficiency (ID) were treated during the next 10 months with intravenous preparation of IgG. Eight children received doses of 500 mg/kg body weight (group A), while five children received doses of 150 mg/kg (group B) at monthly intervals. After five months of this therapy the average increase of IgG concentration was in group A--395 mg/dl, while in group B--100 mg/dl, the difference being statistically significant. Substitution therapy with intravenous IgG was more effective than therapy with fresh plasma and caused appreciable clinical improvement. Only in one out of 130 cases of intravenous injections mild post-transfusion reaction was observed.

Published
1986

32. Evaluation of cell-mediated and humoral immunity in children suffering from spinal muscular atrophy

Author

M, Migaj, W, Janowicz, G, Krajewska, E, Bernatowska, and K, Madaliński

Subjects
Male, B-Lymphocytes, Rosette Formation, T-Lymphocytes, Immunoglobulins, Infant, Lymphocyte Activation, Muscular Atrophy, Child, Preschool, Humans, Female, Lymphocytes, Child, Respiratory Tract Infections, Skin Tests
Abstract

A study of certain parameters of cellular and humoral immunity of 56 children with spinal muscular atrophy (SMA), treated in Children's Memorial Hospital, was undertaken to explain the observed frequent and serious respiratory tract infections. The main differences between a group of patients and the control group were found in the serum IgA and IgM concentrations, a number of peripheral B cells, and in the response to skin tests. Among all the methods applied, the skin tests seem to provide the best information concerning the child immunity system. The observed abnormalities were almost parallel to the severity of the SMA course.

Published
1986

33. [Evaluation of the immune system in children with chronic hepatitis]

Author

M, Migaj, W, Janowicz, H, Gregorek, E, Bernatowska, B, Mikulska, J, Pawłowska, J, Socha, and K, Madaliński

Subjects
Male, Immunity, Cellular, Adolescent, Child, Preschool, Antibody Formation, Humans, Female, Child, Hepatitis B, Hepatitis, Chronic
Published
1986

34. Immunoglobulin synthesis by lymphocytes of eight immuno-deficient children

Author

E, Bernatowska, A, Górski, G, Korczak-Kowalska, D, Dzierzanowska, and K, Madaliński

Subjects
Male, Rosette Formation, Adolescent, Immunologic Deficiency Syndromes, Immunoglobulins, Lymphocyte Activation, Immunoglobulin A, Immunoglobulin M, Child, Preschool, Immunoglobulin G, Candida albicans, Humans, Lymphocytes, Child, Antibodies, Fungal
Abstract

The group of patients consisted of 4 pairs of male siblings with the family history suggesting X-linked immunodeficiency. The concentration of serum immunoglobulins (Ig) and the titer of anti-E. coli and anti-Candida albicans antibodies was extremely low in comparison to the control group. Only 2 siblings showed normal number of lymphocytes with surface Ig. Four out of 8 children had the increased number of Fc-IgG bearing T cells. Blast transformation of lymphocytes revealed the decreased response to PHA and Con A in 2 children. Cellular immunoglobulin (cIg) synthesis of in vitro stimulated peripheral blood lymphocytes (PBL) was decreased in all 8 children. Prednisolone, when added to the PBL cultures, increased cIg synthesis in 2 children. Thymosin (TFX) caused an enhancement of cIg production by lymphocytes of 4 children. Cowan I--elicited stimulation of PBL was low in all but 2 children. Our data further support the view on the heterogeneity of etiopathogenesis of hypogammaglobulinemia.

Published
1985

36. [Arylsulfatase A and B activity in acute lymphoblastic leukemia in children]

Author

E, Bernatowska

Subjects
Adolescent, Chondro-4-Sulfatase, Child, Preschool, Age Factors, Humans, Infant, Lymphocytes, Sulfatases, Child, Prognosis, Cerebroside-Sulfatase, Leukemia, Lymphoid
Abstract

The activity of arylsulphatase A and B was determined in peripheral blood lymphoblasts in 23 children with acute lymphoblastic leukaemia before starting treatment. A low level of activity was found in the group of leukaemic children with poor prognosis, while in children with better prognostic indices this reactivity was high. The course of changes in this activity was traced also during induction of remission of leukaemia and during 3-year maintenance treatment.

Published
1979

37. Clinical manifestations of various phagocytic defects

Author

E, Bernatowska-Matuszkiewicz, M, Smogorzewskan, Z, Rump, H, Skopczyńska, and K, Madaliński

Subjects
Chemotaxis, Leukocyte, Neutropenia, Phagocytosis, Neutrophils, Child, Preschool, Nitroblue Tetrazolium, Humans, Child, Granulomatous Disease, Chronic, Myelography, Agranulocytosis, Blood Cell Count, Granulocytes
Published
1988

40. Intravenous immunoglobulin therapy of progressive encephalitis in X-linked hypogammaglobulinemia

Author

K. Madalinski and E. Bernatowska

Subjects
Male, X Chromosome, Adolescent, X-linked hypogammaglobulinemia, Genetic Linkage, business.industry, Immunization, Passive, Echovirus Infections, General Medicine, medicine.disease, Intravenous Immunoglobulin Therapy, Agammaglobulinemia, Pediatrics, Perinatology and Child Health, Immunology, Encephalitis, Humans, Medicine, business

41. National experience with adenosine deaminase deficiency related SCID in Polish children.

Author

Dąbrowska-Leonik N, Piątosa B, Słomińska E, Bohynikova N, Bernat-Sitarz K, Bernatowska E, Wolska-Kuśnierz B, Kałwak K, Kołtan S, Dąbrowska A, Goździk J, Ussowicz M, and Pac M

Subjects
Infant, Newborn, Humans, Child, Adenosine Deaminase genetics, Poland, Retrospective Studies, Intercellular Signaling Peptides and Proteins, Disease Progression, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency therapy, Severe Combined Immunodeficiency genetics
Abstract

Introduction: Deficiency of adenosine deaminase (ADA) manifests as severe combined immunodeficiency (SCID), caused by accumulation of toxic purine degradation by-products. Untreated patients develop immune and non-immune symptoms with fatal clinical course. According to ESID and EBMT recommendations enzyme replacement therapy (ERT) should be implemented as soon as possible to stabilize the patient's general condition, normalize transaminases, treat pulmonary proteinosis, bone dysplasia, and protect from neurological damage. Hematopoietic stem cell transplantation (HSCT) from a matched related donor (MRD) is a treatment of choice. In absence of such donor, gene therapy (GT) should be considered. HSCT from a matched unrelated donor (MUD) and haploidentical hematopoietic stem cell transplantation (hHSCT) are associated with worse prognosis., Material and Methods: We retrospectively evaluated the clinical course and results of biochemical, immunological and genetic tests of 7 patients diagnosed in Poland with ADA deficiency since 2010 to 2022., Results: All patients demonstrated lymphopenia affecting of T, B and NK cells. Diagnosis was made on the basis of ADA activity in red blood cells and/or genetic testing. Patients manifested with various non-immunological symptoms including: lung proteinosis, skeletal dysplasia, liver dysfunction, atypical hemolytic-uremic syndrome, and psychomotor development disorders. Five patients underwent successful HSCT: 3 patients from matched unrelated donor, 2 from matched sibling donor, and 1 haploidentical from a parental donor. In 4 patients HSCT was preceded by enzyme therapy (lasting from 2 to 5 months). One patient with multiple organ failure died shortly after admission, before the diagnosis was confirmed. None of the patients had undergone gene therapy., Conclusions: It is important to diagnose ADA SCID as early as possible, before irreversible multi-organ failure occurs. In Poland HSCT are performed according to international immunological societies recommendations, while ERT and GT are less accessible. Implementation of Newborn Screening (NBS) for SCID in Poland could enable recognition of SCID, including ADA-SCID., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dąbrowska-Leonik, Piątosa, Słomińska, Bohynikova, Bernat-Sitarz, Bernatowska, Wolska-Kuśnierz, Kałwak, Kołtan, Dąbrowska, Goździk, Ussowicz and Pac.)

Published
2023
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42. Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021.

Author

Abolhassani H, Avcin T, Bahceciler N, Balashov D, Bata Z, Bataneant M, Belevtsev M, Bernatowska E, Bidló J, Blazsó P, Boisson B, Bolkov M, Bondarenko A, Boyarchuk O, Bundschu A, Casanova JL, Chernishova L, Ciznar P, Csürke I, Erdős M, Farkas H, Fomina DS, Galal N, Goda V, Guner SN, Hauser P, Ilyina NI, Iremadze T, Iritsyan S, Ismaili-Jaha V, Jesenak M, Kelecic J, Keles S, Kindle G, Kondratenko IV, Kostyuchenko L, Kovzel E, Kriván G, Kuli-Lito G, Kumánovics G, Kurjane N, Latysheva EA, Latysheva TV, Lázár I, Markelj G, Markovic M, Maródi L, Mammadova V, Medvecz M, Miltner N, Mironska K, Modell F, Modell V, Mosdósi B, Mukhina AA, Murdjeva M, Műzes G, Nabieva U, Nasrullayeva G, Naumova E, Nagy K, Onozó B, Orozbekova B, Pac M, Pagava K, Pampura AN, Pasic S, Petrosyan M, Petrovic G, Pocek L, Prodeus AP, Reisli I, Ress K, Rezaei N, Rodina YA, Rumyantsev AG, Sciuca S, Sediva A, Serban M, Sharapova S, Shcherbina A, Sitkauskiene B, Snimshchikova I, Spahiu-Konjusha S, Szolnoky M, Szűcs G, Toplak N, Tóth B, Tsyvkina G, Tuzankina I, Vlasova E, and Volokha A

Subjects
Infant, Newborn, Humans, Administration, Intravenous, Educational Status, Egypt, Europe, Immunoglobulin G
Abstract

Introduction: The J Project (JP) physician education and clinical research collaboration program was started in 2004 and includes by now 32 countries mostly in Eastern and Central Europe (ECE). Until the end of 2021, 344 inborn errors of immunity (IEI)-focused meetings were organized by the JP to raise awareness and facilitate the diagnosis and treatment of patients with IEI., Results: In this study, meeting profiles and major diagnostic and treatment parameters were studied. JP center leaders reported patients' data from 30 countries representing a total population of 506 567 565. Two countries reported patients from JP centers (Konya, Turkey and Cairo University, Egypt). Diagnostic criteria were based on the 2020 update of classification by the IUIS Expert Committee on IEI. The number of JP meetings increased from 6 per year in 2004 and 2005 to 44 and 63 in 2020 and 2021, respectively. The cumulative number of meetings per country varied from 1 to 59 in various countries reflecting partly but not entirely the population of the respective countries. Altogether, 24,879 patients were reported giving an average prevalence of 4.9. Most of the patients had predominantly antibody deficiency (46,32%) followed by patients with combined immunodeficiencies (14.3%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1 each. The number of patients was remarkably higher that those reported to the ESID Registry in 13 countries. Immunoglobulin (IgG) substitution was provided to 7,572 patients (5,693 intravenously) and 1,480 patients received hematopoietic stem cell therapy (HSCT). Searching for basic diagnostic parameters revealed the availability of immunochemistry and flow cytometry in 27 and 28 countries, respectively, and targeted gene sequencing and new generation sequencing was available in 21 and 18 countries. The number of IEI centers and experts in the field were 260 and 690, respectively. We found high correlation between the number of IEI centers and patients treated with intravenous IgG (IVIG) (correlation coefficient, cc, 0,916) and with those who were treated with HSCT (cc, 0,905). Similar correlation was found when the number of experts was compared with those treated with HSCT. However, the number of patients treated with subcutaneous Ig (SCIG) only slightly correlated with the number of experts (cc, 0,489) and no correlation was found between the number of centers and patients on SCIG (cc, 0,174)., Conclusions: 1) this is the first study describing major diagnostic and treatment parameters of IEI care in countries of the JP; 2) the data suggest that the JP had tremendous impact on the development of IEI care in ECE; 3) our data help to define major future targets of JP activity in various countries; 4) we suggest that the number of IEI centers and IEI experts closely correlate to the most important treatment parameters; 5) we propose that specialist education among medical professionals plays pivotal role in increasing levels of diagnostics and adequate care of this vulnerable and still highly neglected patient population; 6) this study also provides the basis for further analysis of more specific aspects of IEI care including genetic diagnostics, disease specific prevalence, newborn screening and professional collaboration in JP countries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abolhassani, Avcin, Bahceciler, Balashov, Bata, Bataneant, Belevtsev, Bernatowska, Bidló, Blazsó, Boisson, Bolkov, Bondarenko, Boyarchuk, Bundschu, Casanova, Chernishova, Ciznar, Csürke, Erdős, Farkas, Fomina, Galal, Goda, Guner, Hauser, Ilyina, Iremadze, Iritsyan, Ismaili-Jaha, Jesenak, Kelecic, Keles, Kindle, Kondratenko, Kostyuchenko, Kovzel, Kriván, Kuli-Lito, Kumánovics, Kurjane, Latysheva, Latysheva, Lázár, Markelj, Markovic, Maródi, Mammadova, Medvecz, Miltner, Mironska, Modell, Modell, Mosdósi, Mukhina, Murdjeva, Műzes, Nabieva, Nasrullayeva, Naumova, Nagy, Onozó, Orozbekova, Pac, Pagava, Pampura, Pasic, Petrosyan, Petrovic, Pocek, Prodeus, Reisli, Ress, Rezaei, Rodina, Rumyantsev, Sciuca, Sediva, Serban, Sharapova, Shcherbina, Sitkauskiene, Snimshchikova, Spahiu-Konjusha, Szolnoky, Szűcs, Toplak, Tóth, Tsyvkina, Tuzankina, Vlasova and Volokha.)

Published
2022
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43. Lack of relationship between 25-hydoxyvitamin D concentration and a titer of antibodies to hepatitis B surface antigen in children under 12 years of age.

Author

Dabrowska-Leonik N, Sawicka-Powierza J, Bernatowska E, Pac M, Bernat-Sitarz K, Heropolitanska-Pliszka E, Pietrucha B, WolskaKusnierz B, Lewandowicz-Uszynska A, and Mikoluc B

Subjects
Child, Humans, Child, Preschool, Hepatitis B Surface Antigens, Immunization, Secondary, Vaccination, Hepatitis B Antibodies, Vitamins, Vitamin D, Hepatitis B Vaccines, Hepatitis B
Abstract

The effect of vitamin D levels on the response to the hepatitis B vaccine in childhood and the induced levels of antibodies against the hepatitis B surface antigen (anti-HBs) is not yet well understood. The study aimed to investigate the relationship between age, serum 25-hydroxyvitamin D (25(OH)D) concentration and anti-HBs titer among children under 12 years old. Serum 25(OH)D concentration and anti-HBs titer were determined in 352 healthy Caucasian children with the average age of 4.2 (2.5; 6.3) years. All children were vaccinated with 3 doses of hepatitis B vaccine (Engerix-B, GlaxoSmithKline Pharmaceuticals Limited) in infancy according to the Centers for Disease Control and Prevention recommendations. Only 14.5% of children had an optimal concentration of 25(OH)D ≥ 30 ng/mL and 71.9% children had a seroprotective anti-HBs titer ≥ 10 mIU/mL. Significant negative correlations were found between 25(OH)D, anti-HBs titer and age (r = -0.420, p = 0.000; r = -0.425, p = 0.000, respectively), and a weak positive correlation between 25(OH)D concentration and anti-HBs titer (r = 0.243, p = 0.000). Analysis of six clusters of children demonstrated that age is the main factor affecting anti-HBs titer. One third of children under 12 years of age had nonprotective anti-HBs titer < 10 mIU/mL and around 40% had vitamin D deficiency. We conclude that vitamin D status has no impact on anti-HBs titer in children vaccinated against hepatitis B virus in infancy. Age, so time since the receipt of the last dose of hepatitis B vaccine, is the main factor influencing a decline in anti-HBs titer., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Dabrowska-Leonik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2022
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44. BCG Moreau Polish Substrain Infections in Patients With Inborn Errors of Immunity: 40 Years of Experience in the Department of Immunology, Children's Memorial Health Institute, Warsaw.

Author

Bernatowska E, Pac M, Heropolitańska-Pliszka E, Pietrucha B, Dąbrowska-Leonik N, Skomska-Pawliszak M, Bernat-Sitarz K, Krzysztopa-Grzybowska K, Wolska-Kuśnierz B, Bohynikova N, Augustynowicz E, Augustynowicz-Kopeć E, Korzeniewska-Koseła M, Wieteska-Klimczak A, Książyk J, Jackowska T, van den Burg M, Casanova JL, Picard C, and Mikołuć B

Abstract

Objective: We aimed to assess BCG (Bacillus Calmette-Guérin) complications in patients with Inborn Errors of Immunity (IEI), according to the inherited disorders and associated immunological defects, as well as the different BCG substrains., Material: We studied adverse reactions to the locally-produced BCG Moreau vaccine, analyzed in patients with IEI diagnosed between 1980 and 2020 in the Department of Immunology, Children's Memorial Health Institute (CMHI), Warsaw. These results were compared with previously published studies., Results: Significantly fewer disseminated BCG infections (BCGosis) were found in 11 of 72 (15%) SCID (Severe Combined Immunodeficiency) NK (Natural Killer)-phenotype patients, when compared with the 119 out of 349 (34%) ( p = 0.0012) patients with SCID with BCG in other countries. Significantly fewer deaths caused by BCGosis were observed ( p = 0.0402). A significantly higher number of hematopoietic stem cell transplantations (HSCTs) were performed in the CMHI study ( p = 0.00001). BCGosis was found in six patients with Mendelian susceptibility to mycobacterial diseases (MSMD). Other patients with IEI prone to BCG complications, such as CGD (Chronic Granulomatous Disease), showed no case of BCGosis., Conclusion: The BCG Moreau substrain vaccine, produced in Poland since 1955, showed genetic differences with its parental Brazilian substrain together with a superior clinical safety profile in comparison with the other BCG substrains, with no BCGosis in patients with IEI other than SCID and MSMD. Our data also confirmed significantly fewer cases of BCGosis and deaths caused by BCG infection in patients with SCID with this vaccine substrain. Finally, they confirmed the protecting role of NK cells, probably via their production of IFN-γ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bernatowska, Pac, Heropolitańska-Pliszka, Pietrucha, Dąbrowska-Leonik, Skomska-Pawliszak, Bernat-Sitarz, Krzysztopa-Grzybowska, Wolska-Kuśnierz, Bohynikova, Augustynowicz, Augustynowicz-Kopeć, Korzeniewska-Koseła, Wieteska-Klimczak, Książyk, Jackowska, van den Burg, Casanova, Picard and Mikołuć.)

Published
2022
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45. Correction to: A Multi-center, Open-Label, Single-Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency.

Author

Santamaria M, Neth O, Douglass JA, Krivan G, Kobbe R, Bernatowska E, Grigoriadou S, Bethune C, Chandra A, Horneff G, Borte M, Sonnenschein A, Kralickova P, Ramón SS, Langguth DD, Gonzalez-Granado LI, Alsina L, Querolt M, Griffin R, Hames C, Mondou E, Price J, Sanz A, and Lin J

Published
2022
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46. A Multi‑Center, Open‑Label, Single‑Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency.

Author

Santamaria M, Neth O, Douglass JA, Krivan G, Kobbe R, Bernatowska E, Grigoriadou S, Bethune C, Chandra A, Horneff G, Borte M, Sonnenschein A, Kralickova P, Ramón SS, Langguth D, Gonzalez-Granado LI, Alsina L, Querolt M, Griffin R, Hames C, Mondou E, Price J, Sanz A, and Lin J

Subjects
Adolescent, Adult, Child, Humans, Immunoglobulin G therapeutic use, Immunoglobulins, Intravenous, Immunologic Factors therapeutic use, Infusions, Subcutaneous, Immunologic Deficiency Syndromes diagnosis, Immunologic Deficiency Syndromes drug therapy
Abstract

Purpose: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI)., Methods: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured., Results: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate., Conclusions: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI., (© 2021. The Author(s).)

Published
2022
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47. Experimental and Numerical Investigation into Failure Modes of Tension Angle Members Connected by One Leg.

Author

Bernatowska E and Ślęczka L

Abstract

This paper presents the results of experimental and numerical tests on angle members connected by one leg with a single row of bolts. This study was designed to determine which failure mode governs the resistance of such joints: net section rupture or block tearing rupture. Experimental tests were insufficient to completely identify the failure modes, and it was necessary to conduct numerical simulations. Finite element analysis of steel element resistance based on rupture required advanced material modelling, taking into account ductile initiation and propagation of fractures. This was realised using the Gurson-Tvergaard-Needleman porous material model, which allows for analysis of the joint across the full scope of its behaviour, from unloaded state to failure. Through experimental testing and numerical simulations, both failure mechanisms (net section and block tearing) were examined, and an approach to identify the failure mode was proposed. The obtained results provided experimental and numerical evidence to validate the strength function used in design standards. Finally, the obtained results of the load capacity were compared with the design procedures given in the Eurocode 3's current and 2021 proposed editions.

Published
2021
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48. Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) with a New Pathogenic Variant in TNFRSF1A Gene in a Family of the Adult Male with Renal AA Amyloidosis-Diagnostic and Therapeutic Challenge for Clinicians.

Author

Zegarska J, Wiesik-Szewczyk E, Hryniewiecka E, Wolska-Kusnierz B, Soldacki D, Kacprzak M, Sobczynska-Tomaszewska A, Czerska K, Siedlecki P, Jahnz-Rozyk K, Bernatowska E, Zagozdzon R, and Paczek L

Abstract

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) belongs to systemic autoinflammatory diseases (AIDs). Many of these syndromes are genetically conditioned and can be inherited. Diagnosis relies on clinical symptoms and should be confirmed by genetic testing. One of the most serious complications is AA amyloidosis. We present the diagnostic route of a 33-year-old male with AA amyloidosis and his children, leading to diagnosis of monogenic autoinflammatory syndrome, confirmed by genetic analysis. A novel variant of the in-frame insertion type in one allele of TNFRSF1A gene was found by whole exome sequencing and confirmed by Sanger sequencing, which allowed a diagnosis of TRAPS. Three-dimensional modeling was used to assess the structural changes introduced into TNFR1 molecule by the insertion. The analysis of the 3D model revealed that accommodation of the 4AA insert induces misalignment of three cysteine bridges (especially the C70-C96 bridge) in the extracellular domain, leading to putatively misfolded and improperly functioning TNFR1. Three of the patient's daughters inherited the same variant of the TNFRSF1A gene and presented TRAPS symptoms. TRAPS is a very rare disease, but in the presence of suggestive symptoms the genetic diagnostic workout should be undertaken. Early diagnosis followed by appropriate clinical management can prevent irreversible complications.

Published
2021
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49. Interstitial Lung Disease in Children With Selected Primary Immunodeficiency Disorders-A Multicenter Observational Study.

Author

Pac M, Bielecka T, Grzela K, Komarnicka J, Langfort R, Koltan S, Dabrowska-Leonik N, Bernat-Sitarz K, Pronicki M, Dmenska H, Pituch-Noworolska A, Mikoluc B, Piatosa B, Tkaczyk K, Bernatowska E, Wojsyk-Banaszak I, and Krenke K

Subjects
Adolescent, Adrenal Cortex Hormones therapeutic use, Age Factors, Child, Child, Preschool, Female, Humans, Immunosuppressive Agents therapeutic use, Lung Diseases, Interstitial diagnosis, Lung Diseases, Interstitial drug therapy, Male, Poland, Primary Immunodeficiency Diseases diagnosis, Primary Immunodeficiency Diseases drug therapy, Retrospective Studies, Treatment Outcome, Lung Diseases, Interstitial etiology, Primary Immunodeficiency Diseases complications
Abstract

Primary immunodeficiencies (PIDs) are rare disorders of the immune system encompassing inborn errors of immunity. Primary antibody deficiencies constitute the largest group of PID with common variable immunodeficiency (CVID) being the most common symptomatic form. Combined immunodeficiencies (CID) accompanied by antibody deficiency can mimic CVID and these patients need the verification of the final diagnosis. Respiratory involvement, especially interstitial lung disease (ILD), poses a relevant cause of morbidity and mortality among patients with PID and in some cases is the first manifestation of immunodeficiency. In this study we present a retrospective analysis of a group of children with primary immunodeficiency and ILD - the clinical, radiological, histological characteristics, treatment strategies and outcomes. Eleven children with PID-related ILD were described. The majority of them presented CVID, in three patients CID was recognized. All patients underwent detailed pulmonary diagnostics. In eight of them histological analysis of lung biopsy was performed. We noted that in two out of 11 patients acute onset of ILD with respiratory failure was the first manifestation of the disease and preceded PID diagnosis. The most common histopathological diagnosis was GLILD. Among the analyzed patients three did not require any immunosuppressive therapy. All eight treated children received corticosteroids as initial treatment, but in some of them second-line therapy was introduced. The relevant side effects in some patients were observed. The study demonstrated that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and second-line treatment may be necessary., (Copyright © 2020 Pac, Bielecka, Grzela, Komarnicka, Langfort, Koltan, Dabrowska-Leonik, Bernat-Sitarz, Pronicki, Dmenska, Pituch-Noworolska, Mikoluc, Piatosa, Tkaczyk, Bernatowska, Wojsyk-Banaszak and Krenke.)

Published
2020
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50. The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256&#95;257delAA Founder Variant in Slavic Countries.

Author

Sharapova SO, Skomska-Pawliszak M, Rodina YA, Wolska-Kuśnierz B, Dabrowska-Leonik N, Mikołuć B, Pashchenko OE, Pasic S, Freiberger T, Milota T, Formánková R, Szaflarska A, Siedlar M, Avčin T, Markelj G, Ciznar P, Kalwak K, Kołtan S, Jackowska T, Drabko K, Gagro A, Pac M, Naumova E, Kandilarova S, Babol-Pokora K, Varabyou DS, Barendregt BH, Raykina EV, Varlamova TV, Pavlova AV, Grombirikova H, Debeljak M, Mersiyanova IV, Bondarenko AV, Chernyshova LI, Kostyuchenko LV, Guseva MN, Rascon J, Muleviciene A, Preiksaitiene E, Geier CB, Leiss-Piller A, Yamazaki Y, Kawai T, Walter JE, Kondratenko IV, Šedivá A, van der Burg M, Kuzmenko NB, Notarangelo LD, Bernatowska E, and Aleinikova OV

Subjects
Adolescent, Child, Child, Preschool, Female, Gene Frequency, Humans, Incidence, Infant, Infant, Newborn, Male, Phenotype, Polymorphism, Genetic, Retrospective Studies, Treatment Outcome, Young Adult, DNA-Binding Proteins genetics, Genotype, Homeodomain Proteins genetics, Immunologic Deficiency Syndromes genetics, Nuclear Proteins genetics, Sequence Deletion genetics, White People
Abstract

Background: Variants in recombination-activating genes ( RAG ) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency. Objective: We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the RAG defects in populations inhabiting South, West, and East Slavic countries. Methods: Demographic, clinical, and laboratory data were collected from RAG -deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined in vitro by flow cytometry-based assay. Results: Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of RAG deficiencies, including SCID ( n = 20), OS ( n = 37), and LS/CID ( n = 25) phenotypes. Sixty-seven (81.7%) patients carried RAG1 and 15 patients (18.3%) carried RAG2 biallelic variants. We estimate that the minimal annual incidence of RAG deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% ( n = 47) of patients with RAG1 variants carried p.K86Vfs * 33 (c.256&#95;257delAA) allele, either in homozygous ( n = 18, 27%) or in compound heterozygous ( n = 29, 43%) form. The majority (77%) of patients with homozygous RAG1 p.K86Vfs * 33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous RAG1 p.K86Vfs * 33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion: We propose that RAG1 p.K86Vfs * 33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of RAG1 founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival., (Copyright © 2020 Sharapova, Skomska-Pawliszak, Rodina, Wolska-Kuśnierz, Dabrowska-Leonik, Mikołuć, Pashchenko, Pasic, Freiberger, Milota, Formánková, Szaflarska, Siedlar, Avčin, Markelj, Ciznar, Kalwak, Kołtan, Jackowska, Drabko, Gagro, Pac, Naumova, Kandilarova, Babol-Pokora, Varabyou, Barendregt, Raykina, Varlamova, Pavlova, Grombirikova, Debeljak, Mersiyanova, Bondarenko, Chernyshova, Kostyuchenko, Guseva, Rascon, Muleviciene, Preiksaitiene, Geier, Leiss-Piller, Yamazaki, Kawai, Walter, Kondratenko, Šedivá, van der Burg, Kuzmenko, Notarangelo, Bernatowska and Aleinikova.)

Published
2020
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