Features of the course of chronic spontaneous urticaria in patients with Common variable immune deficiency and hypogammaglobulinemia.

Chronic spontaneous urticaria is a common disease that can be associated with various autoimmune, infectious (viral, bacterial, parasitic) and non-infectious inflammatory diseases, as well as occur in the symptom complex of other diseases, such as primary immunodeficiencies (PID). Currently, data about the features of the course of chronic spontaneous urticaria in patients with PID are accumulating. In this article we present two clinical cases of patients with common variable immune deficiency and one clinical case of a patient with hypogammaglobulinemia, suffering from chronic spontaneous urticaria. The article describes peculiar properties of IVIG replacement therapy at the course of urticaria in these patients. The discussion section presents data from the world literature and offers key provisions for further investigations.

COVID-19 Infection in a Patient with Common Variable Immunodeficiency: Experience with Favipiravir and Intravenous Immunoglobulin

ABSTRACT Data regarding COVID-19 infection in patients with common variable immunodeficiency (CVID) are limited. Herein, we present a 28-year-old male patient with CVID admitted for intravenous immunoglobulin (IVIG) replacement with myalgia and a productive cough. A nasopharyngeal swab for the SARS CoV-2 polymerase chain reaction assay was positive. Chest computed tomography was consistent with COVID-19 pneumonia. The patient refused hospitalization and the applicable treatment for COVID-19. Although he was prescribed IVIG, he had a lapse in IVIG replacement due to supply problems. The patient was later brought to the emergency room due to the deterioration of his general condition with dyspnea, tachypnea, shortness of breath, cough, and fever five days after the initial presentation. He was treated with favipiravir and IVIG and had a positive outcome. Results of COVID-19 infection in CVID patients are diverse, possibly due to underlying genetic defects. Although our patient had an increased risk for severe disease due to CVID, a lapse in IVIG replacement, and obesity, he did not require intensive care or intubation. Further studies are needed to determine and develop treatment strategies for COVID-19 infection in patients diagnosed with CVID. Keywords: COVID-19, common variable immunodeficiency disorders, immunodeficiencies, immunoglobulin, convalescent plasma

Первичные иммунодефициты: общий вариабельный иммунодефицит

This review provides data on the most common primary immunodeficiency of the humoral immunity – the general variable immunodeficiency, the characteristics of the clinical manifestations of this pathology, as well as the features of diagnostics and treatment. The disease can develop at any age. However, around the world there is a late diagnostics of primary immunodeficiencies. The disease is characterized by a polymorphic nonspecific picture including lesions of almost all body systems. Infectious pathology and oncological diseases are the main cause of death in this group of patients. Early detection of patients with general variable immunodeficiency and the prescription of IVIG replacement therapy will increase the duration and improve their quality of life.

Efficiency of complex therapy in patients with a- and hypogammaglobulinemia

Objective:assessment of the effectiveness of the use of Polymuramil in complex with IVG therapy with patients with CVID and ХLA with insufcient replacement therapy.Materials and methods:there were 10 patients with insufcient effectiveness of IVIG replacement therapy, receiving complex IVIG therapy and immunomodulator Polymuramil at a dose of 200 μg / 0.5 ml No. 5 intramuscularly every other day, under study. Surface and intracellular markers of cells of the congenital and acquired immune response, serum immunoglobulins of class A, M, G - in the radial immunodiffusion in the Mancini gel, the oxygen-dependent metabolic activity of neutrophils in NST-test were assessed with the help of flow cytometry, before and afer 3 months and a comparative analysis of the obtained data was conducted.Results:analysis of the data revealed a signifcant increase in markers of lymphocyte activation, which indicates the induction properties of the studied immunomodulator by increasing the activation potentials of the cellular link of adaptive immunity in patients with primary immunodefciency.Summary:in patients with a genetically mediated defect of the humoral immunity against the background of complex therapy with the use of Polymuramil, the activation of congenital and adaptive immunity is registered, which is confrmed, in addition to laboratory indexes, by a decrease in the frequency of exacerbations of chronic inflammatory diseases.

Primary hypogammaglobulinemia: The impact of early diagnosis in lung complications

Summary Objective: To describe clinical features, tomographic findings and pulmonary function in pediatric patients with primary hypogammaglobulinemia (PH). Method: A retrospective cohort study of children with PH who received intravenous immunoglobulin (IVIG) and prophylactic antibiotics between 2005 and 2010. Epidemiological and clinical features, computed tomography (CT) findings, and spirometric data were compared, assuming a 5% significance level. Results: We evaluated 30 patients with PH. After the start of IVIG replacement, there was a decline in the frequency of pneumonia (p<0.001). The 11 patients with bronchiectasis in their first CT scan were older at diagnosis (p=0.001) and had greater diagnostic delay (p=0.001) compared to patients without bronchiectasis. At the end of the study, 18 patients had bronchiectasis and 27 also had other lung disorders, alone or in combination. The Bhalla score was applied to the last CT scan of 16 patients, with a median score of 11 (range 7-21), with a positive correlation between the score and the number of pneumonias after the start of treatment (r=0.561; p=0.024). The score was also correlated with forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) values in 13/16 patients, with negative correlation to FEV1 previously to bronchodilator (r=-0.778; p=0.002) and after bronchodilator (r =-0.837; p<0.001) and FVC (r=-0.773; p=0.002). Conclusion: Pulmonary complications were common in this cohort, despite the decrease in the frequency of pneumonia with treatment. Early investigation of patients with recurrent infections for primary immunodeficiencies can reduce the frequency of these complications. The monitoring of changes in spirometry may indicate the need to carry out radiological investigation.

B Cell Reconstitution after Gene Therapy in Patients with Wiskott Aldrich Syndrome and Comparison with Mismatched Allogeneic Hematopoietic Stem Cell Transplantation

Background. Wiskott Aldrich Syndrome (WAS) is a rare primary immunodeficiency associated with thrombocytopenia, eczema, severe infectious and autoimmune complications, and lymphomas. Mismatched allogeneic hematopoietic stem cell transplantation (HSCT) is an alternative for patient lacking an HLA-matched donor but is associated with an increased frequency of complications. Moreover low lymphoid and myeloid chimerism is related to a higher rate of autoimmunity and thrombocytopenia. Recent gene therapy (GT) trials showed that gene-corrected autologous CD34+ cells infusion could be an appropriate therapeutic approach for these patients. It has been recently shown that B cell homeostasis is altered in WAS. As the B cell reconstitution participates to the restoration of immunological competence, a comprehensive study of this compartment after GT and the comparison with mismatched allogeneic HSCT is crucial. Objective. To perform a longitudinal study of B cell reconstitution in WAS patients after lentiviral vector-mediated GT, compared to mismatched allogeneic HSCT. Methods. Five patients (age 0.8-15.5 years) underwent GT at our center since 2011(follow-up 1.5-4.2 years) after near-myeloablative and immunosuppressive conditioning regimen with (n=3) or without (n=2) anti-CD20 administration. Patient 2 (P2) died 7 months after GT from a pre-existing infectious complication. Eleven patients undergoing mismatched allogeneic HSCT (age 0.6-10.9 years) at the same center were studied (follow-up 5.1-14.7 years). Longitudinal B cell assessment included B cell count before and after treatment, and the following subsets: switched memory (SM, CD19+ CD27+ IgD-), marginal zone (MZ, CD19+ CD27+ IgD+), naives (CD19+ CD27- IgD+), transitional (CD19+ CD27- IgD+ CD24high CD38high), circulating plasma cells (CD19+ CD27+ IgD- CD27high CD38high) and CD21low B cells (CD19+ CD21low CD38-), a subset abnormally expanded in WAS. Quantification of the B cell replication history was assessed through k-deleting recombination excision circles (KRECs). Analyses were compared to age-matched controls. WAS protein (WASP) expression and vector copy number (VCN) were measured in sorted B cells. Results. All alive GT patients show stable engraftment of functionally corrected lymphoid cells, without adverse events. Transduced B cells number and WASP expression increased progressively after GT. Absolute B cell count attained normal values in all the patients, and correlates with WASP expression and VCN in B cells. IgM levels are below normal ranges in four patients. P3 and P4 attained a B-cell phenotype within normal ranges; P3 discontinued intravenous immunoglobulin (IvIg) replacement. No expansion of CD21low B cells was observed. P1 and P5 (follow-up 18 months) present a variable defect in SM, naives and/or MZ B cells. P1 recently developed autoimmune manifestations; no significant changes were observed concomitantly. A defect in B cell lymphopoiesis was observed before GT as measured by KRECs analysis, normalizing after GT (P1, P3 and P4). Several complications were recorded in patients undergoing mismatched allogeneic HSCT, including dysimmunity, arthritis, developmental deficit and infections. Total B cell count normalized in eight patients, IgM levels were low in three. Among patients with available information, four still remain under IvIg replacement. Four patients developed a mixed lymphoid and myeloid chimerism, variably associated with low B cell count, low IgM and IvIg replacement. A complete B cell assessment for these patients is ongoing. Conclusions. B cell transgene expression is obtained after lentiviral vector-mediated GT in WAS patients and is associated with improved B cell lymphopoiesis. A correct B cell phenotype is observed in two patients who did not receive rituximab prior GT. The question whether this is related to the treatment will need a longer follow-up to be answered. Patients undergoing mismatched allogeneic HSCT present a higher frequency of complications. Although a higher proportion of these patients discontinued IvIg replacement, B cell reconstitution is not optimal. Analysis of patients in particular with mixed chimerism will provide important information in the setting of GT. The analysis of B cell reconstitution after GT and mismatched allogeneic HSCT deserves particular attention in the assessment of immunological reconstitution. Disclosures No relevant conflicts of interest to declare.

Home gammaglobulin therapy: a patient survey of intravenous and subcutaneous options in Canada

Introduction: For close to half a century immunoglobulin replacement therapy has been the main therapy for patients unable to produce functioning antibodies. To date, both subcutaneous (SC) and intravenous delivery methods have been successful at effectively and safely replacing immunoglobulin. Home intravenous and SC therapy programs have been established and have gained attention, but the true motivation and frequency of switching from traditional hospital-based treatment to these alternatives remains unknown. This study aims to determine the willingness of patients in Canada to switch to a home-based gammaglobulin treatment program by quantifying related experiences and preferences. Methods: A cohort of 169 patients in Ontario currently on hospital-based intravenous immunoglobulin (IVIG) replacement therapy (referral centers or community hospitals) were sent a 2.5 page survey consisting of 25 questions. Data were collected and statistically analyzed using Fisher, χ2, and McNemar tests, where P < 0.05 was considered statistically significant. Results: Ninety-one patients responded and most agreed to consider home therapy regardless of the administration route, based on recommendations from an immunologist (IVIG, P = 0.006; SC, P < 0.001). Patients preferred switching to home IVIG rather than to SC (P = 0.01), but their concerns regarding home healthcare costs were more prominent with IVIG (P = 0.01). The main concern with current intravenous therapy was the overall loss of time (P = 0.0001), whereas for home therapy it was the loss of supervision (P = 0.0009) and possible associated costs. Patients considered home treatment more convenient, as it is less time consuming (P = 0.01), and this was perceived as an improvement in quality of life (P = 0.001). It was considered less convenient because it may be unsafe and (or) more expensive. Conclusion: This survey demonstrates that home intravenous therapy maybe the preferred option for patients with antibody deficiency in Ontario, provided this decision was supported by a specialist in the field, secured supervision was available, and it was not associated with personal expenses. Statement of novelty: The first study to examine patient willingness to try a new route of gammaglobulin administration at home.

HIPERBILIRUBINEMIA PADA NEONATUS

Hyperbilirubinemia is an increase of the blood bilirubin level due to physiological or non-physiologic factors, which is clinically characterized by jaundice. Bilirubin is produced in the reticuloendothelial system as the end product of heme catabolism through an oxidation-reduction reaction. Due to its hydrophobic nature, unconjugated bilirubin is carried in the plasma, tightly bound to albumin. In the liver, bilirubin is transported into hepatocytes, bound to ligandin. After being excreted to the small intestine through the bile ducts, bilirubin undergoes a reduction to become colorless tetrapyrole due to the action of intestinal microbes.This unconjugated bilirubin can be reabsorbed into the circulation; therefore, it increases total plasma bilirubin. The treatments of hyperbilirubinemia in neonati are phototherapy, intravenous immunoglobulin (IVIG), replacement transfusion, temporary breastfeeding cessation, and medical therapy. Keywords: hyperbilirubinemia, bilirubin, biliverdin, enterohepatic cycle. Abstrak: Hiperbilirubinemia ialah terjadinya peningkatan kadar bilirubin dalam darah, baik oleh faktor fisiologik maupun non-fisiologik, yang secara klinis ditandai dengan ikterus. Bilirubin diproduksi dalam sistem retikuloendotelial sebagai produk akhir dari katabolisme heme dan terbentuk melalui reaksi oksidasi reduksi. Karena sifat hidrofobiknya, bilirubin tak terkonjugasi diangkut dalam plasma, terikat erat pada albumin. Ketika mencapai hati, bilirubin diangkut ke dalam hepatosit, terikat dengan ligandin. Setelah diekskresikan ke dalam usus melalui empedu, bilirubin direduksi menjadi tetrapirol tak berwarna oleh mikroba di usus besar. Bilirubin tak terkonjugasi ini dapat diserap kembali ke dalam sirkulasi, sehingga meningkatkan bilirubin plasma total. Pengobatan pada kasus hiperbilirubinemia dapat berupa fototerapi, intravena immunoglobulin (IVIG), transfusi pengganti, penghentian ASI sementara, dan terapi medikamentosa. Kata kunci: hiperbilirubinemia, bilirubin, biliverdin, siklus enterohepatik.