Thrombocytopenia in common variable immunodeficiency patients - clinical course, management, and effect of immunoglobulins.

Common variable immunodeficiency (CVID) is a primary immunodeficiency of humoral immunity with heterogeneous clinical features. Diagnosis of CVID is based on hypogammaglobulinaemia, low production of specific antibodies, and disorders of cellular immunity. The standard therapy includes replacement of specific antibodies with human immunoglobulin, prophylaxis, and symptomatic therapy of infections. High prevalence of autoimmunity is characteristic for CVID, most commonly: thrombocytopaenia and neutropaenia, celiac disease, and systemic autoimmune diseases. The study included seven children diagnosed with CVID and treated with immunoglobulin substitution from 2 to 12 years. Thrombocytopenia was diagnosed prior to CVID in four children, developed during immunoglobulin substitution in three children. In one boy with CVID and thrombocytopaenia, haemolytic anaemia occurred, so a diagnosis of Evans syndrome was established. Therapy of thrombocytopaenia previous to CVID included steroids and/or immunoglobulins in high dose, and azathioprine. In children with CVID on regular immunoglobulin substitution, episodes of acute thrombocytopaenia were associated with infections and were treated with high doses of immunoglobulins and steroids. In two patients only chronic thrombocytopaenia was noted. Splenectomy was necessary in one patient because of severe course of thrombocytopaenia. The results of the study indicated a supportive role of regular immunoglobulin substitution in patients with CVID and chronic thrombocytopaenia. However, regular substitution of immunoglobulins in CVID patients did not prevent the occurrence of autoimmune thrombocytopaenia episodes or exacerbations of chronic form. In episodes of acute thrombocytopaenia or exacerbations of chronic thrombocytopaenia, infusions of immunoglobulins in high dose are effective, despite previous regular substitution in the replacing dose.

T lymphocytes and NK cells in X-linked agammaglobulinemia.

Seven boys with diagnosis of X-linked agammaglobulinemia on regular substitution of immunoglobulins were included into study. The patients showed episodes of infections but the clinical course was mild with good response to antibiotics. All patients developed, with time, the chronic sinusitis with proliferation of mucous membrane, two patients showed bronchiectases. The number of T lymphocytes, ratio of CD4:CD8 subpopulations, response to stimulation and NK number were assayed with flow cytometry and cell culture. Results showed CD4:CD8 ratio within normal value in majority of patients, reverse ratio in 2 boys, increased number of activated T cells (CD3/HLA-DR) in one of them. The number of NK cells was different from lack of these cells to high number. Response of T cells to stimulation (mitogens and CD3) were normal in majority of assays. There were no associations between clinical course and observed changes in T or NK cell populations. Further studies on number and function of NK cells are needed.

Occurrence of autoantibodies for gastrointestinal autoimmune diseases in children with common variable immune deficiency and selected IgA deficiency.

INTRODUCTION: Selected IgA deficiency (IgAD) and common variable immune deficiency (CVID) are humoral immunity deficiencies frequent in children. In both these types of immunodeficiency, autoimmune diseases are present in 20-30% of patients, but the disease profiles are different between adults and children. Autoimmune diseases of the gastrointestinal tract (IBD) and celiac disease are typical for children with IgAD and CVID. Diagnosis is based on clinical symptoms, histology of jejunum and antibodies often preceding the onset of disease. However, the diagnosis of IBD and celiac disease is difficult in immune deficiency patients due to weaker or absent production of antibodies, and different jejunum histology, particular in CVID patients. AIM: Detection of antibodies for autoimmune diseases in children with diagnosis of CVID and IgAD. MATERIAL AND METHODS: The study included 43 children with CVID and 63 children with IgAD diagnosis. Antibodies typical for celiac disease (for endomysium, tissue transglutaminase and gliadin) were tested in IgA class (CVID patients), IgG class (IgAD, CVID patients) and found in 16 patients (3 - CVID, 13 - IgAD). RESULTS: Antibodies for IBD (for Saccharomyces cerevisiae antigen - ASCA, goblet cells - Gab, neutrophil's cytoplasm - ANCA, pancreatic cells - Pab) were noted in 17 patients (7 - CVID, 10 - IgAD). Celiac disease was diagnosed in two children with mild and unspecific clinical symptoms followed by introduction of a gluten-free diet. The remaining children with present antibodies but without clinical symptoms involving the gastrointestinal tract are under careful clinical observation with antibody assay every 6 months. CONCLUSIONS: The antibodies are produced despite impaired humoral immunity but the level might be low so the lower limit of positive results is postulated.

[The use of human immunoglobulins--adverse reactions]. / Stosowanie preparatów immunoglobulin ludzkich--objawy niepozadane.

The primary immunodeficiency, mainly humoral immunity, secondary immunodeficiency and autoimmune diseases are the indications for immunoglobulins substitution. The prolonged substitution in primary immunodeficiency includes regular intravenous infusion of immunoglobulins in 0.4-0.6 g/kg of body weight every 21-28 days. The purpose of such substitution is decrease of frequency and diminishes the clinical course of infections. The high-dose use of immunoglobulins (1-2 g/kg body weight) is preferred in autoimmune diseases based on suppressive and anti-inflammatory activity of immunoglobulins. The subcutaneous administration of immunoglobulins is an alternative to intravenous way, but the singular dose (0.1 g/kg body weight) is too low for suppressive and anti-inflammatory activity of immunoglobulins, so this substitution is indicated in primary immunodeficiency only. The adverse events of immunoglobulins differentiate because of time of occurrence and clinical character. The rapid symptoms occurred just after beginning of infusion and often present the clinical features of anaphylactoid reaction. During the infusion the occurring adverse symptoms are mild and the life-threatening situations are very rare. The next periods of typical adverse reaction are 24-48 hrs after infusion, 72 hrs and later. The mechanisms leading to adverse reaction to immunoglobulins are based on presence of IgG dimmers, stimulating high production of pro-inflammatory cytokines by immunocompetent cells. High level of cytokines is associated with high fever, chills, flu-like symptoms, feeling malaise and sick. The reaction of anti-IgA antibodies present in patient serum with IgA in immunoglobulins preparation is responsible for moderate and severe adverse clinical symptoms. The late adverse events present the symptoms of aseptic meningo-encephalitis. In case of adverse events the stopping of infusion, additions saline/ glucose infusion, anti-histaminic drugs of I and II generation and steroids are used. Severe adverse events are indication for withdraw the immunoglobulins intravenous infusions. In these patients the subcutaneous way of immunoglobulins substitution is an alternative with hope that low singular dose and slow uptake may be better tolerated.

[Stimulation of the immune system in children]. / Stymulacja ukladu odpornosci u dzieci.

The basic mechanisms of specific immune response in children to pathogens with characteristics of cells involved in the process were described. The characteristics of commonly used stimulators (thymus-derived peptides, bacterial lysates and ribosoms, glukans) and the mechanisms of action, target cells were shown. In general remarks the limitations of immunostimulation in children with recurrent infections with or without known immunodeficiency were stressed.

Familial occurrence of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome.

INTRODUCTION: Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder with an autosomal-dominant pattern of inheritance and low fatality rate but significant lifelong morbidity. MATERIALS AND METHODS: A 27-year-old mother of two children has been suffering from severe neutropenia and recurrent infections with the diagnosis of sporadic WHIM syndrome established by sequencing the CXCR4 gene and the finding of a heterozygous 1000 C-->T nonsense mutation in the second CXCR4 exon. The first child was an apparently healthy boy delivered at full term. Umbilical cord blood cells were obtained for genetic analysis. Peripheral blood cells were also analyzed at 8 months of life. Both analyses revealed the same mutation as that of his mother. The child was in a good condition, manifesting neutropenia without infections until 11 months of life. He subsequently developed pneumonia requiring a more aggressive treatment. After that, the regular substitution of immunoglobulins (IVIGs) and G-CSF has been preventing serious infections. Six months ago the second boy was delivered who also demonstrated neutropenia without severe infections. Genetic studies using cord blood and also peripheral blood cells in the fourth month showed an identical mutation of the CXCR4 gene as in his mother. Moreover, the mother and her first son demonstrated monocytopenia. RESULTS: The results indicate that genetic defects connected with WHIM syndrome may influence not only the granulocyte, but also the monocytic lineage. Moreover, a perinatal diagnosis of WHIM syndrome made by sequencing the CXCR4 gene should be performed in cases where either parent is known to be affected with this disease. CONCLUSIONS: This would facilitate an earlier detection of the deficiency in children, thereby allowing a more comprehensive follow-up and administration of appropriate therapy.